Histamine H2-receptor Blockers Research Articles

Anti-edematous effects of epinastine, cetirizine and its enantiomers in λ-carrageenan-induced edema in rat hind paw.

Urticaria is induced by the histamine released from mast cells which develops wheals (edema) as a visual feature. In clinical practice, second-generation histamine H1 -receptor blockers are routinely used as the first-line symptomatic treatment for urticaria. Nevertheless, not much research has directly examined the second-generation histamine H1-receptor blockers' ability to reduce edema. In this study, we directly evaluated the anti-edematous activities of three second-generation histamine H1-receptor blockers available in the market (epinastine hydrochloride, cetirizine hydrochloride, and levocetirizine hydrochloride) using a λ-carrageenan-induced footpad edema model. One hour before the induction of edema with 1% λ -carrageenan injection, all second-generation histamine H1 -receptor blockers (5, 10, 50 and 100 mg/kg) were subcutaneously administered to rats. At 0.5 and 3 hours after λ -carrageenan administration, the edema volume was evaluated using a Plethysmometer. Epinastine hydrochloride significantly suppressed the edema growth in a dose-dependent manner. Cetirizine hydrochloride showed a slight anti-edematous effect, while levocetirizine significantly inhibited the development of edema in a dose-dependent manner. On the other hand, dextrocetirizine did not prevent edema from growing. In summary, second-generation histamine H1 -receptor blockers, at least those examined in this study, may be able to reduce the clinical symptoms of urticaria associated with edema. Levocetirizine hydrochloride is also anticipated to have stronger anti-edematous effects than cetirizine hydrochloride because levocetirizine is responsible for cetirizine's anti-edematous activity.

Inhibitors of gastric acid secretion increase oxidative stress and matrix metalloproteinase-2 activity leading to vascular remodeling.

The use of inhibitors of gastric acid secretion (IGAS), especially proton pump inhibitors (PPI), has been associated with increased cardiovascular risk. While the mechanisms involved are not known, there is evidence supporting increased oxidative stress, a major activator of matrix metalloproteinases (MMP), as an important player in such effect. However, there is no study showing whether other IGAS such as histamine H2-receptor blockers (H2RB) cause similar effects. This study aimed at examining whether treatment with the H2RB ranitidine promotes oxidative stress resulting in vascular MMP activation and corresponding functional and structural alterations in the vasculature, as compared with those found with the PPI omeprazole. Male Wistar rats were treated (4 weeks) with vehicle (2% tween 20), omeprazole (10 mg/Kg/day; i.p.) or ranitidine (100 mg/Kg/day; gavage). Then the aorta was collected to perform functional, biochemical, and morphometric analysis. Both ranitidine and omeprazole increased gastric pH and oxidative stress assessed in situ with the fluorescent dye dihydroethidium (DHE) and with lucigenin chemiluminescence assay. Both IGAS augmented vascular activated MMP-2. These findings were associated with aortic remodeling (increased media/lumen ratio and number of cells/μm2). Both IGAS also impaired the endothelium-dependent relaxation induced by acetylcholine (isolated aortic ring preparation). This study provides evidence that the H2RB ranitidine induces vascular dysfunction, redox alterations, and remodeling similar to those found with the PPI omeprazole. These findings strongly suggest that IGAS increase oxidative stress and matrix metalloproteinase-2 activity leading to vascular remodeling, which helps to explain the increased cardiovascular risk associated with the use of those drugs.

Association Between Risk of Clostridium difficile Infection and Duration of Proton Pump Inhibitor or H2-Receptor Antagonist Use in Hospitalized Patients.

Limited studies have evaluated the association between Clostridium difficile infection (CDI) and the duration of proton pump inhibitor (PPI) or histamine H2-receptor blocker (H2RA) use and provided a cutoff duration for PPI or H2RA use to mitigate a substantially increased risk of CDI. We aimed to evaluate these associations in hospitalized patients using a nationwide insurance claims database. We conducted a nested case-control study to identify cases with a first ever record of CDI in a study cohort undergoing PPI or H2RA therapy from the National Health Insurance Database from 2012 to 2018. Each case was matched with one control by age, sex, and calendar year. We used conditional logistic regression to estimate the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC ROC). Youden's Jstatistic was used to identify the optimal cutoff duration in days for PPI or H2RA use. In the main analysis, the AUC ROC was 0.64 (95%CI 0.63-0.66) and optimal cutoff duration was 15days for PPI users. The AUC ROC was 0.63 (95%CI 0.62-0.64) and optimal cutoff duration was 16days for H2RA users. In the sensitivity analyses, the results were similar to those of the main analysis, and the optimal cutoff duration was in the range of 14-15days. The optimal cutoff duration for PPI and H2RA use was about 2weeks. It is necessary to be cautious regarding the risk of CDI in patients taking PPIs or H2RAs for longer than 2weeks.

Optimization of the treatment of patients with severe chronic urticaria

Severe chronic urticaria (SCU) is a common disease that burdens the lives of millions of people, reduces their quality of life, and imposes a significant economic burden not only on the health care system, but also directly on the patient. To date, a single approach regarding the optimal dosing of omalizumab in this cohort of patients has not been determined. The purpose of the work: based on the assessment of the quality of life of patients with SCU and dynamic clinical and laboratory observation, to study the effectiveness and prove the feasibility of using the minimum dose of 150 mg for omalizumab according to the scheme every 21 days intramuscularly three times, which will allow to optimize the treatment tactics of these patients and reduce the economic burden of the cost of their treatment. In a prospective single-center study lasting 33 weeks, 104 patients with a diagnosis of SCU were included. All patients underwent a general clinical examination, quality of life indicators using the SKINDEX-29 questionnaire were studied; blood tryptase level once before the start of treatment using ImmunoCAP was determined, the level of total IgE in blood serum using an immunochemical method with electrochemiluminescence detection before and after the end of treatment was determined. The patients were divided into two groups: Group 1 (54 people) had a relapse of urticaria within 3 to 6 months after completing a course of second-generation histamine H1-receptor blockers and received a course of omalizumab at a dose of 150 mg intramuscularly every three weeks three times. Group 2 (50 people) had a relapse of urticaria no earlier than 6 months after the previous course of second-generation histamine H1-receptor blockers and received desloratadine, 5 mg during the first four weeks and 20 mg during the next four weeks. Indicators of urticaria activity (UAS7) and quality of life (SKINDEX-29) in patients were determined before the start of treatment and at each of the visits (on the 10th, 31st and 52nd days of therapy when treated with omalizumab and five and nine weeks after initiation of desloratadine therapy), and UAS7 was assessed six months after the end of treatment. Methods of descriptive and analytical statistics were used to process the obtained data. According to our data, patients with SCU are mostly people of working age, more than half of whom have a history of the disease for five years or more, in 70% of cases of a valid study, they are characterized by an increased content of total IgE and have a low level of indicators according to the questionnaire SKINDEX-29 at the level of physical symptoms, emotional sphere and functioning. We found that in patients of observation Groups 1 and 2, after the treatment, the level of total IgE in blood serum decreased statistically significantly. In patients of Group 1, the appointment of omalizumab in the minimum dose made it possible to ensure the control of urticaria symptoms already after the first injection in 15% of cases, and after the third injection there was a stable remission with the absence of urticaria symptoms during six months of follow-up in 92.3% of patients, against the existing 24% of subjects of Group 2, who after therapy according to UAS7 had very severe and severe symptoms. After the completion of treatment in patients of Group 2, nine weeks after the initiation of desloratadine therapy according to the SKINDEX-29 questionnaire, 44% of cases and 46% of very severe negative effects of urticaria on the emotional sphere and functioning remained, respectively; and in 46% of cases there was a low quality of life according to the generalized assessment of the impact of the disease at the level of "severe". At the same time, among the patients of Group 1, after completion of omalizumab therapy on the 52nd day of observation, no case of severe or very severe negative impact of urticaria on the quality of life was registered in any of the domains. Thus, the effectiveness and justified expediency of prescribing omalizumab treatment of 150 mg with an interval of 21 days three times in patients with SCU, who have a recurrence of chronic dermatosis within 3 to 6 months after the second-generation histamine H1-receptor blocker therapy has been confirmed.

Crystalline and amorphous famotidine malate as pathways to prevent polymorphic transformation with improved dissolution

Famotidine (FMT) is an orally administered histamine H2-receptor blocker with limited bioavailability since it exhibits low solubility and low permeability. In addition, the recent withdrawal of ranitidine from the market, makes famotidine an interesting candidate to obtain solid forms with improved pharmacokinetic performance. In this work, crystal engineering concepts and the co-amorphous formation strategy were applied to obtain two novel solids. Crystalline famotidine malate (FMT-MT) and a vitreous phase (FMT-MTa) were prepared by solvent evaporation and mechanochemical synthesis, respectively. FMT-MT (monoclinic, S.G. P21/n) crystallizes with one FMT and one co-former molecules in the asymmetric unit forming a (R228) structural motif. FMT-MT resulted in a salt by proton transfer from one malic carboxylic group to the guanidine moiety of FMT. The three-dimensional packing is described as undulating layers of alternated FMT+ and MT- running along the a direction. FMT-MTa shows the inherent features of amorphous phases according to powder X-ray diffraction and DSC analysis. The higher physical stability was found for amorphous samples maintained at 4 °C up to 60 days. The solubility assays in water, indicate that FMT-MT and FMT-MTa are 2.02 and 2.68-fold more soluble than the marketed polymorph, whereas similar values were obtained in simulated gastric fluid.

Simultaneous determination of 10 first-generation histamine h1 receptor blockers in feeds by ultra-high-performance liquid chromatography triple quadrupole ion trap hybrid mass spectrometer.

A method for simultaneous determination of 10 first-generation histamine H1 receptor blockers in feeds by ultra-high-performance liquid chromatography triple quadrupole mass spectrometry combined with solid phase extraction. Instrument conditions, extraction solvents, and purification methods have been optimized. Under the optimum conditions, these analytes were separated effectively at 6min. These feeds have been extracted by acid acetonitrile and purified by mixed cation exchange solid-phase extraction. The performance of this method meets the requirements of veterinary residue detection in feeds in China. It is appropriate for the confirmatory monitoring and quantitative analysis of 105 feed samples, five kinds of histamine H1 receptor blockers have been detected in 10 samples.

Antiulcerogenic Potential of the Ethanolic Extract of Ceiba speciosa (A. St.-Hil.) Ravenna Evaluated by In Vitro and In Vivo Studies.

Gastrointestinal diseases, such as peptic ulcers, are caused by a damage in the gastric mucosa provoked by several factors. This stomach injury is regulated by many inflammatory mediators and is commonly treated with proton-pump inhibitors, histamine H2 receptor blockers and antacids. However, various medicinal plants have demonstrated positive effects on gastric ulcer treatment, including plants of the Ceiba genus. The aim of this study was to evaluate the antiulcer and anti-inflammatory activities of the stem bark ethanolic extract of Ceiba speciosa (A. St.-Hil.) Ravenna. We performed a preliminary quantification of phenolic compounds by high-performance liquid chromatography-diode array detection (HPLC-DAD), followed by the prospection of other chemical groups through nuclear magnetic resonance (NMR) spectroscopy. A set of in vitro assays was used to evaluate the extract potential regarding its antioxidant activity (DPPH: 19.83 ± 0.34 µg/mL; TPC: 307.20 ± 6.20 mg GAE/g of extract), effects on cell viability and on the release of TNF-α in whole human blood. Additionally, in vivo assays were performed to evaluate the leukocyte accumulation and total protein quantification in carrageenan-induced air pouch, as well as the antiulcerogenic effect of the extract on an ethanol-induced ulcer in rats. The extract contains flavonoids and phenolic compounds, as well as sugars and quinic acid derivatives exhibiting potent antioxidant activity and low toxicity. The extract reduced the release of TNF-α in human blood and inhibited the activity of p38α (1.66 µg/mL), JAK3 (5.25 µg/mL), and JNK3 (8.34 µg/mL). Moreover, it reduced the leukocyte recruitment on the pouch exudate and the formation of edema, reverting the effects caused by carrageenan. The extract presented a significant prevention of ulcer formation and a higher reduction than the reference drug, Omeprazole. Therefore, C. speciosa extract has demonstrated relevant therapeutic potential for the treatment of gastric diseases, deserving the continuation of further studies to unveil the mechanisms of action of plant bioactive ingredients.

An expert opinion on antacids: A review of its pharmacological properties and therapeutic efficacy

Acidity caused by common gastric conditions such as non-ulcer dyspepsia, duodenal ulcer, gastric ulcer, stress gastritis, gastroesophageal reflux disease (GERD), pancreatic insufficiency, bile acid-mediated diarrhea, biliary reflux, and constipation can be treated by administration of potent and efficacious acid suppressant (anti-secretory) agents such as antacids, histamine H2 receptor blockers, and proton pump inhibitors (PPIs). Antacids provide symptomatic relief from hyperacidity as well as other associated conditions by neutralizing the gastric acid directly, thereby raising the gastric pH, attenuating the pepsin activity, restoring acid-base balance, and increasing prostaglandin and bicarbonate secretion. The effectiveness of antacids is determined by its acid neutralizing capacity (ANC) and buffering capacity. Antacids containing a combination of aluminum hydroxide, magnesium hydroxide, and other ingredients such as those present in Digene showed better therapeutic efficacy even at low dosage with fewer side effects, persistent increase in gastric pH, faster and longer duration of pain relief, and fast relief from gas. Various clinical studies suggest that to obtain fast symptomatic relief, the treating physician can utilize antacids with the highest neutralizing capacities like Digene.

Potentially Inappropriate Medication Use in Patients with Dementia.

The objective of this study was to characterize the epidemiology of using potentially inappropriate medications associated with dementia exacerbation (DPIMs) in elderly outpatients with dementia. Electronic medical records were retrospectively reviewed for geriatric patients with dementia who were prescribed at least one medication in 2016 at a tertiary, university-affiliated hospital. The 2015 Beers criteria were used to define DPIMs. Logistic regression was performed to identify factors associated with prescribing DPIMs in patients with dementia. Among 2100 patients included in our study, 987 (47.0%) patients were prescribed at least one DPIM. Benzodiazepines were the most frequently prescribed DPIM followed by anticholinergics, histamine H2-receptor blockers, and zolpidem. The risk of prescribing DPIMs was significantly increased in female patients (odds ratio (OR) 1.355) with polypharmacy (OR 5.146) and multiple comorbidities (OR 1.129) (p < 0.05 for all). Coexistence of Parkinson’s disease (OR 1.799), mood disorder (OR 1.373), or schizophrenia (OR 4.116) in patients with dementia further increased the likelihood of receiving DPIMs. In conclusion, DPIMs were commonly used in elderly patients with dementia in Korea with benzodiazepines most frequently prescribed followed by anticholinergics. Female patients using polypharmacy with multiple comorbidities should be closely monitored to minimize unnecessary DPIM use and, ultimately, DPIM-related harms.

LYTIC COCKTAIL ATTENUATES CATECHOLAMINE SURGE AFTER SEVERE BURNS BY BLOCKING HISTAMINE H1 RECEPTOR/PKA/CREB/TYROSINE HYDROXYLASE SIGNALING IN CHROMAFFIN CELLS.

Severe burns develop a catecholamine surge, inducing severe damage to the organism, raising the possibility of multisystem organ failure, and even death. The mechanisms of catecholamine surge have not been fully elucidated, and few strategies are generally acceptable to reduce catecholamine surge postburn. Thus, it is valuable to investigate the underlying mechanisms of catecholamine surge postburn to develop targeted interventions to attenuate it. We have found that the lytic cocktail alleviates the surge of catecholamine and organ injury after severe burn; however, the underlying mechanisms were still unclear. Moreover, the lytic cocktail has side effects, such as significant arterial hypotension and breathing depression, limiting its clinical application. This study aims to investigate the therapeutic mechanism of the lytic cocktail in regulating catecholamine levels postburn. We find that promethazine, a classic histamine H1 receptor blocker and a component of the lytic cocktail, can effectively reduce catecholamine surge and organ injury postburn. Our study confirms that blood histamine levels increase after severe burns. We find that histamine can amplify the catecholamine surge by elevating tyrosine hydroxylase expression and catecholamine synthesis in chromaffin cells through the histamine H1 receptor/Protein Kinase A /cAMP-response element binding protein signaling pathway. In summary, for the first time, we find that histamine plays a vital role in catecholamine surge postburn. We also confirm that the lytic cocktail effectively alleviates catecholamine surge and organ injury postburn through promethazine.

Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: Are we there yet?

Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety.

Histamine Potentiates SARS-CoV-2 Spike Protein Entry Into Endothelial Cells.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes coronavirus disease (COVID-19) is one of the most serious global health crises in recent history. COVID-19 patient symptoms range from life-threatening to mild and asymptomatic, which presents unique problems in identifying, quarantining, and treating the affected individuals. The emergence of unusual symptoms among survivors, now referred to as “Long COVID”, is concerning, especially since much about the condition and the treatment of it is still relatively unknown. Evidence so far also suggests that some of these symptoms can be attributed to vascular inflammation. Although famotidine, the commonly used histamine H2 receptor (H2R) blocker, was shown to have no antiviral activity, recent reports indicate that it could prevent adverse outcomes in COVID-19 patients. Histamine is a classic proinflammatory mediator, the levels of which increase along with other cytokines during COVID-19 infection. Histamine activates H2R signaling, while famotidine specifically blocks H2R activation. Investigating the effects of recombinant SARS-CoV-2 spike protein S1 Receptor-Binding Domain (Spike) on ACE2 expression in cultured human coronary artery endothelial cells, we found that the presence of histamine potentiated spike-mediated ACE2 internalization into endothelial cells. This effect was blocked by famotidine, protein kinase A inhibition, or by H2 receptor protein knockdown. Together, these results indicate that histamine and histamine receptor signaling is likely essential for spike protein to induce ACE2 internalization in endothelial cells and cause endothelial dysfunction and that this effect can be blocked by the H2R blocker, famotidine.

Sleep disorders and their correction in patients with chronic back pain

Back pain and insomnia (insomnia) significantly impair the quality of life of patients. Pain contributes to the development of sleep disorders and vice versa, poor quality sleep increases pain. Sleep disorders are widespread in the population, and in chronic pain syndrome, almost 70% of patients suffer from insomnia. The National Sleep Association singles out pain as one of the leading causes of sleep disorders. The article discusses a typical clinical case of the combination and interaction of chronic pain syndrome and insomnia. A patient with acute back pain developed a sleep disorder for which therapy was not carried out. The prescribed standard therapy for back pain, which included a non-steroidal anti-inflammatory drug, muscle relaxant, made it possible to relieve pain in a short time. However, the patient’s insomnia not only persisted, but also progressed, which led to the appearance of symptoms of asthenia in the form of fatigue, irritability, decreased performance, and ultimately significantly reduced the quality of life. In order to normalize sleep, the patient was prescribed a histamine H1 receptor blocker from the ethanolamine group, namely the drug Doxylamine. Follow-up observation for 1 year showed no exacerbation of back pain and sleep disturbances. In the treatment of patients with chronic back pain, it is necessary to pay attention to the presence of sleep disturbances and provide appropriate therapy. Today, three groups of hypnotics are used in clinical practice: melatonin receptor agonists (insufficient effectiveness in acute sleep disorders), benzodiazepines (addictive and addictive), and antihistamines. The modern drug Doxylamin belongs to the group of antihistamine hypnotics, has a good efficacy and safety profile and is included in the domestic recommendations for the treatment of insomnia.

Connections between Immune-Derived Mediators and Sensory Nerves for Itch Sensation.

Although histamine is a well-known itch mediator, histamine H1-receptor blockers often lack efficacy in chronic itch. Recent molecular and cellular based studies have shown that non-histaminergic mediators, such as proteases, neuropeptides and cytokines, along with their cognate receptors, are involved in evocation and modulation of itch sensation. Many of these molecules are produced and secreted by immune cells, which act on sensory nerve fibers distributed in the skin to cause itching and sensitization. This understanding of the connections between immune cell-derived mediators and sensory nerve fibers has led to the development of new treatments for itch. This review summarizes current knowledge of immune cell-derived itch mediators and neuronal response mechanisms, and discusses therapeutic agents that target these systems.

Pediatric Mastocytosis: An Update.

Mastocytosis is a rare clonal disorder characterized by excessive proliferation and accumulation of mast cells (MC) in various organs and tissues. Cutaneous mastocytosis (CM), the most common form in children, is defined when MC infiltration is limited to the skin. In adults, the most common form is systemic mastocytosis (SM), characterized by MC proliferation and accumulation in organs, such as bone marrow, lymph nodes, liver, and spleen.1 Genetic aberrations, mainly the KIT D816V mutation, play a crucial role in the pathogenesis of mastocytosis, enhancing MC survival and subsequent accumulation in organs and tissues.2,3 CM includes three forms: solitary mastocytoma, maculopapular cutaneous mastocytosis (MPCM), and diffuse cutaneous mastocytosis (DCM). In most children with CM, skin lesions regress spontaneously around puberty; unfortunately, it is not always a self-limiting disease.4 Even if SM occurs occasionally, all children with mastocytosis require planned follow-up over time. Children with mastocytosis often suffer from MC mediator-related symptoms, the most common of which is itching, often triggered by rubbing the lesions. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers. Treatment with H1 and H2 histamine receptor blockers on demand and the availability of epinephrine auto-injectors for the patients to use in case of severe anaphylactic reactions are recommended.

Drug Repurposing Patent Applications April–June 2021

Drug Repurposing Patent Applications April–June 2021

Molecular Background, Clinical Features and Management of Pediatric Mastocytosis: Status 2021.

Pediatric mastocytosis is a heterogeneous disease characterized by accumulation of mast cells in the skin and less frequently in other organs. Somatic or germline mutations in the KIT proto-oncogene are detected in most patients. Cutaneous mastocytosis is the most common form of the disease in children. In the majority of cases, skin lesions regress spontaneously around puberty. However, in few patients, mastocytosis is not a self-limiting disease, but persists into adulthood and can show signs of systemic involvement, especially when skin lesions are small-sized and monomorphic. Children with mastocytosis often suffer from mast cell mediator-related symptoms. Severe hypersensitivity reactions can also occur, mostly in patients with extensive skin lesions and blistering. In a substantial number of these cases, the triggering factor of anaphylaxis remains unidentified. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers, treatment with H1 and H2 histamine receptor blockers, and equipment of patients and their families with epinephrine auto-injectors for use in severe anaphylactic reactions. Advanced systemic mastocytosis occurs occasionally. All children with mastocytosis require follow-up examinations. A bone marrow investigation is performed when advanced systemic mastocytosis is suspected and has an impact on therapy or when cutaneous disease persists into adulthood.

Abstract PS5-16: Impact of drug-drug interaction on palbociclib serum levels: Interest of therapeutic drug monitoring

Abstract Background: The CDK4/6 inhibitors palbociclib is prescribed in association with hormonal therapy for the management of metastatic breast cancer patients. Like most oral targeted drug, therapeutic drug monitoring may be used for personalize their dosage. Using a recently published dosing technique (LC-MS/MS), we aimed at evaluating the correlation between first-cycle palbociclib plasma exposition and co-medications in order to evaluate drug-drug interaction (DDI) impact under palbociclib treatment.Methods: This is an open-label phase 4 study conducted in female subjects with first-line metastatic breast cancer (NCT04025541) treated with a palbociclib-aromatase inhibitor association. Plasma concentration of palbociclib was assessed at 24 hours postdose (plasma trough concentration Ctrough) at day 15 of first cycle of treatment. A dedicated pharmacist consultation allowed the determination of clinical covariates of interest, such as weight, body surface area, ethnicity, food intake, co-medications use and DDI before Palbociclib initiation and retrospectively at the end of clinical trial. Patients were classified then according to their risk of DDI potentially leading to inhibition of CYP3A4 and/or P-glycoprotein and gastric pH increase by gastric acid-suppressive (GAS) agents (such as proton pump inhibitors, histamine H2-receptor blockers or alginic acid). Relevant drug known to have an inhibition of CYP3A4 and/or P-glycoprotein or pH-modification activity were checked in databases (e.g. DDI predictor®, Drugs.com®, Pubmed®). Results: To date, after Ctrough analysis of the 35 first cases, the geometric mean (± standard deviation [min-max]) of palbociclib plasma Ctrough was 79.5 ng/ml (± 26.1% [43.6 ng/mL - 133 ng/mL]) at day 15, similar to what reported in the PALOMA trials. No correlation between plasma concentration and body weight, body area or also age of the patients was found in our cohort. Regarding ethnicity, all the included patients were from Caucasian origin. 31% of patients (11/35) were identified of taking drugs that could cause DDI CYP3A4 and P-glycoprotein inhibition mediated (amlodipine n=3, simvastatin n=3, losartan n=2, fluconazole n=1, atorvastatin n=1, ivabradine n=1). These potential DDI interactions were associated with a significantly higher palbociclib concentration DDI subgroup (102 ng/mL vs 69 ng/mL) (p=0.000272) (Table 1). No CYP3A4 and/or P-glycoprotein inductor were reported in cohort. 1.4% of patients (5/35) were identified of taking GAS agents (pantoprazole n=2, ranitidine n=2, alginic acid n=1). We found a significantly reduction of palbociclib concentration (59.2 ng/mL vs 79.8 ng/mL) (p=0.048) in patients taking GAS medications (Table 1). Conclusion : These preliminary results, in real-life settings, obtained with our recently-published HPLC-MS/MS method, give important information on palbociclib monitoring and pharmacokinetic variability. DDI appear to have a significant impact on palbociclib plasma exposure, GAS agents are already know to modified palbociclib absorption. Additional studies are needed to characterize palbociclib plasma concentration variations between patients, and their clinical impact on efficacy and safety. The study is ongoing and will evaluate additional potential clinical and biological impact of DDI on neutropenia occurrence, on a larger population of patients. Table 1: Patients’ plasma palbociclib concentration (day 15 of cycle 1 of treatment).Plasma palbociclib concentrations (ng/ml), global cohort (n=35)Geometric mean (CV%) (min;max)79.5 (26.1%) (43.6;133)Plasma palbociclib concentrations (ng/ml), cohort with DDI CYP3A4 and P-gp mediated (n=11)Geometric mean (CV%)102 (24.3%)Plasma palbociclib concentrations (ng/ml), cohort without DDI CYP3A4 and P-gp mediated (n=24)Geometric mean (CV%)69 (19.8%)Plasma palbociclib concentrations (ng/ml), cohort with GAS treatment (n=5)Geometric mean (CV%)59.2 (15.9%)Plasma palbociclib concentrations (ng/ml), cohort without GAS treatment (n=30)Geometric mean (CV%)82.9 (26.1%) Citation Format: Fanny Leenhardt, Matthieu Gracia, Catherine Perrin, Claudia Muracciole-Bich, Bénédicte Marion, Celine Roques, Marie Alexandre, Nelly Firmin, Stephane Pouderoux, Litaty Mbatchi, Celine Gongora, William Jacot, Alexandre Evrard. Impact of drug-drug interaction on palbociclib serum levels: Interest of therapeutic drug monitoring [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-16.

Alteration of Activation Energy of a Reaction in the Catalase of Human Erythrocyte by Cimetidine, an In vitro Thermokinetic Study

Background: Hydrogen peroxide is normally formed during the metabolic pathway of the body. It is a toxic compound for vital cells, which can oxidize many macromolecules and cause damage in cells. Catalase can degrade H2O2 in cells and prevent cell injury. Cimetidine is a histamine H2 receptor blocker which decreases the release of stomach acid and is used for gastrointestinal diseases. Cimetidine inhibited catalase by mixed inhibition. Objective: In this study, the effect of temperature on the binding of cimetidine to human erythrocyte catalase was investigated and kinetic factors of the binding were determined. Results: Dixon plot confirmed the mixed type of inhibition and determined the Ki of the drug. The maximum activity of the enzyme was observed at 30°C. Arrhenius plot demonstrated that the activation energy of the enzyme reaction in the absence and presence of cimetidine was about 4.7 and 8.13 kJ/mol, respectively. The temperature coefficient (Q30-40) was determined as about 1.11 and 1.09 in the absence and presence of cimetidine. Conclusion: Cimetidine was able to increase the activation energy of the reaction of catalase, which confirmed the inhibition of the enzyme based on the kinetic results.

Gastric Perforation due to Candida Infection in Association with Prolonged Proton Pump Inhibitor Use: A Report of Two Cases

Fungus as a cause of gastric perforation is very rare. Very low pH of stomach usually does not support fungal growth. It is usually associated with immunocompromised state or is seen in debilitated patients like patients receiving steroid therapy, patients with Diabetes Mellitus (DM) and Human Immunodeficiency Virus (HIV) infection, patients undergoing transplant. Prolonged use of strong antacids can also be a predisposing factor for gastric fungal infection; although this theory is controversial, authors could find few studies which were similar to present study. Here, authors are reporting two cases of gastric perforation leading to peritonitis, in otherwise healthy individuals due to prolonged Proton Pump Inhibitors (PPIs) use, due to Candida infection, in the following case report. Both patients (48-year-old male and 65-year-old female) had history of chronic PPI use, had gastric perforation and underwent exploratory laparotomy. On histopathological examination of perforation edge biopsy yeast forms and few pseudohyphae of Candida species were identified. Postoperatively one of the patients survived with systemic antifungal, antibiotic therapy along with replacement of PPI with histamine H2 receptor blockers. The other patient could not survive and died postoperatively due to septicaemia. Fungal aetiology in gastric perforation should prompt further evaluation to look for underlying cause. This case report highlights the effects of unjust and over use of strong antacids for prolonged period.